Abstract Sex and gender—biological and social constructs—significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) ...and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex‐ and gender‐specific drivers of resilience, including a sex/gender‐oriented review of risk factors, genetics, AD and non‐AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender‐aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender‐specific resilience throughout disease stages. Highlights Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex‐specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex‐specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.
INTRODUCTION
Although large‐scale genome‐wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.
METHODS
We ...conducted a cross‐ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts.
RESULTS
We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non‐Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene‐level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD‐related traits, neuropsychiatric traits, and autoimmune traits.
DISCUSSION
We discovered several novel loci, genes, and genetic correlations associated with late‐life memory performance and decline.
Highlights
Late‐life memory has high heritability that is similar across ancestries.
We discovered four novel variants associated with late‐life memory.
We identified four novel genes associated with late‐life memory.
Late‐life memory shares genetic architecture with psychiatric/autoimmune traits.
BACKGROUND
Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory ...performance remain unclear.
METHODS
We conducted the largest sex‐aware genetic study on late‐life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex‐stratified and sex‐interaction genome‐wide association studies in 24,216 non‐Hispanic White and 3367 non‐Hispanic Black participants.
RESULTS
We identified three sex‐specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ‐SCHIP), including an X‐chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex‐specific pathway and found sex‐specific genetic correlations between memory and cardiovascular, immune, and education traits.
DISCUSSION
This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex‐specific genes, pathways, and genetic correlations that related to late‐life memory.
Highlights
Demonstrated the heritable component of late‐life memory is similar across sexes.
Identified two genetic loci with a sex‐interaction with baseline memory.
Identified an X‐chromosome locus associated with memory decline in females.
Highlighted sex‐specific candidate genes and pathways associated with memory.
Revealed sex‐specific shared genetic architecture between memory and complex traits.
Late-onset Alzheimer's disease (LOAD) is a polygenic disorder with a long prodromal phase, making early diagnosis challenging. Twin studies estimate LOAD as 60-80% heritable, and while common genetic ...variants can account for 30% of this heritability, nearly 70% remains "missing". Polygenic risk scores (PRS) leverage combined effects of many loci to predict LOAD risk, but often lack sensitivity to preclinical disease changes, limiting clinical utility. Our group has built and published on a resilience phenotype to model better-than-expected cognition give amyloid pathology burden and hypothesized it may assist in preclinical polygenic risk prediction. Thus, we built a LOAD PRS and a resilience PRS and evaluated both in predicting cognition in a dementia-free cohort (N=254). The LOAD PRS had a significant main effect on baseline memory (β=-0.18, P=1.68E-03). Both the LOAD PRS (β=-0.03, P=1.19E-03) and the resilience PRS (β=0.02, P=0.03) had significant main effects on annual memory decline. The resilience PRS interacted with CSF Aβ on baseline memory (β=-6.04E-04, P=0.02), whereby it predicted baseline memory among Aβ+ individuals (β=0.44, P=0.01) but not among Aβ- individuals (β=0.06, P=0.46). Excluding APOE from PRS resulted in mainly LOAD PRS associations attenuating, but notably the resilience PRS interaction with CSF Aβ and selective prediction among Aβ+ individuals was consistent. Although the resilience PRS is currently somewhat limited in scope from the phenotype's cross-sectional nature, our results suggest that the resilience PRS may be a promising tool in assisting in preclinical disease risk prediction among dementia-free and Aβ+ individuals, though replication and fine-tuning are needed.
Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the ...cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified n (males) = 2093, n (females) = 2931 and sex-interaction n (both sexes) = 5024 genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04 in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.
Background
Alzheimer’s disease (AD) polygenic risk scores (PRS) are often derived from case/control GWAS, which are typically not sensitive to preclinical disease changes, limiting their clinical ...utility. To overcome this pitfall, we built and evaluated the performance of multiple PRS of AD‐related endophenotypes, including resilience to cognitive impairment in the presence of amyloid.
Method
Four PRS were derived from GWAS of baseline memory, memory decline, cognitive resilience (Dumitrescu et al., 2021), and AD (Kunkle et al. 2019). PRS were built in an independent cohort that was free of dementia, the Vanderbilt Memory and Aging Project (N=255). We used linkage disequilibrium clumping on TOPMed‐imputed genotypes, and a threshold of P=0.01. We ran linear models with baseline memory score as the outcome, and baseline age, sex, and PRS as predictors. Linear mixed effects models, with identical predictors, were used when longitudinal memory was the outcome, letting individual slope and intercept vary. Finally, we tested a CSF Aβ42‐by‐PRS interaction term to assess if PRS modified associations between amyloid and cognition. Sensitivity analyses excluded APOE from PRS calculations.
Result
As expected, the baseline memory PRS related to baseline memory (β=0.12, P=0.04), and the memory decline PRS related to longitudinal memory (β=0.04, P=0.001). Without APOE, the baseline memory PRS and the memory decline PRS results attenuated. The AD PRS related to both baseline memory (β=‐0.19, P=0.002) and longitudinal memory (β=‐0.03, P=0.01), but results attenuated without APOE. The resilience PRS did not have a main effect on baseline or longitudinal memory. However, interestingly, the resilience PRS interacted with CSF Aβ42 on baseline memory (β=‐0.001, P=0.02; Figure 1), whereby the resilience PRS related to memory among amyloid‐positive individuals (β=0.44, P=0.01) but not amyloid‐negative individuals (β=0.06, P=0.46). No other PRS was predictive of memory among amyloid‐positive individuals, and resilience PRS results remained consistent without APOE.
Conclusion
Our results demonstrate that a resilience PRS appears to be predictive of individual cognitive performance downstream of amyloidosis. Future work is needed to replicate this finding, but our preliminary findings highlight the potential utility of resilience PRS for predicting individual risk for AD‐related cognitive impairment during the preclinical stages of disease.
IMPORTANCE: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific ...cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. OBJECTIVE: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. MAIN OUTCOMES AND MEASURES: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. RESULTS: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = −0.071, SE = 0.014; P = 9.6 × 10−7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = −0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. CONCLUSIONS AND RELEVANCE: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.
Abstract
Background
Genetic analyses of cognitive endophenotypes have led to discoveries of novel loci contributing to Alzheimer’s disease (AD) risk. Sex differences are present in cognitive ...trajectories in aging and AD, and these may vary across cognitive domain. However, genetic drivers that may contribute to sex differences in cognitive trajectories have yet to be explored. Thus, we sought to investigate the sex‐specific genetic architecture of cognition.
Method
We leveraged 10 cohorts of cognitive aging and AD to complete this sex‐aware genetic study (N = 31,800; mean age = 73 yrs.; 55% female). Harmonized cognitive scores for memory, executive functioning, and language were derived using confirmatory factor analysis models. We calculated change in cognitive scores over time using a mixed effects model, to facilitate analysis on cognitive decline. We performed GWAS of baseline score and of estimated rate of decline in each domain and in each cohort separately among non‐Hispanic white (NHW) individuals, adjusting for baseline age and genetic principal components. Then we meta‐analyzed the results.
Result
In addition to the well‐characterized
APOE
locus, we identified a genome‐wide significant chromosome 2 locus that was associated with language decline among NHW women (rs13387871: MAF = 0.20; β
women
= 2.97×10
−3
; P
women
= 2.65×10
−9
), but not among male counterparts (β
men
= ‐3.14×10
−4
, P
men
= 0.60). This locus contains multiple eQTLs for
VRK2
, a serine/threonine kinase that has been previously linked to neuropsychiatric disorders, including schizophrenia. Furthermore, the top variant in this locus (rs13387871) was nominally significant for memory decline (β
women
= 1.74×10
−3
, P
women
= 0.01) and for executive functioning decline (β
women
= 7.58×10
−4
, P
women
= 0.02) in meta‐analyses among NHW women.
Conclusion
Our genetic analysis suggests that there may be some genetic drivers of language performance that differ by sex, and that these drivers may be shared to an extent across domains. Our future sex‐aware meta‐analyses will also include 1) non‐Hispanic black (NHB) within ancestry (N = 4,200), 2) cross‐ancestry (NHW + NHB), 3) diagnosis‐stratified, and 4) analysis of X‐chromosome. Planned follow‐up analyses will include gene‐set analyses, heritability tests, and genetic correlation tests. Through our preliminary analysis, we identified a promising locus for further exploration, and this is the first of many steps in elucidating the sex‐specific genetic architecture of cognition across ancestry groups.
Abstract
Background
Memory performance can serve as a strong endophenotype for Alzheimer’s disease (AD) that changes early and continues to decline with disease progression. Yet, the genetic ...architecture of memory is not well characterized in older adults. Here, we build on existing memory GWAS studies by performing predicted gene expression analysis (PrediXcan) among older (60+) individuals from four cohorts of aging and investigate specific gene‐tissue drivers of genetically regulated gene expression associated with memory performance.
Method
Tissue‐specific (49 tissues, 5455 genes) PrediXcan models were built following the method described in Gamazon et al. (Nature Genetics 2015) leveraging model weights derived in GTEx (v8 release, build 38). Baseline and longitudinal memory scores were harmonized leveraging cognitive item‐level data on 19,707 non‐Hispanic White participants from four cohort studies of aging and AD (mean age 75.6±7.7, 55% female) using confirmatory factor analyses models. PrediXcan analyses were run adjusting for age at baseline, sex, and 5 population PCs and then meta‐analyzed using a fixed effects model. Correction for multiple comparisons accounting for all gene‐tissue combinations (267,267) was completed with the false discovery rate procedure (fdr‐p<0.05). Sensitivity analyses excluded all non‐AD dementia and other comorbid conditions (N = 16,373; 57% females).
Result
As expected, several signals emerged from chromosome 19, including 48 gene‐tissue combinations near the APOE locus. Outside of APOE, we identified 20 gene‐tissue combinations from 17 known AD loci and three novel loci: higher predicted PUS7 expression in the caudate (β = ‐0.018, p = 0.034) and higher RP11‐18C3.1 expression in colon (β = ‐0.0165, fdr‐p = 0.034) related to faster cognitive decline, while higher predicted LRRC25 in the nucleus accumbens related to slower cognitive decline (β = 0.009, fdr‐p = 0.015). These signals remain comparable in sensitivity analysis.
Conclusion
We identified multiple candidates for future mechanistic analysis. LRRC25 is a particularly interesting candidate that is differentially expressed in the AD brain, regulates autophagy in myeloid cells, and is in a co‐expression network with other known AD genes in the immune pathway like MS4A4A (
https://agora.adknowledgeportal.org/
). Future work will test for replication of these effects and deconvolve genetically‐regulated versus measured gene expression effects in the AD brain.
Abstract
Background
Alzheimer’s disease (AD) is clinically characterized by disabling cognitive impairment, though substantial variability in cognitive symptoms and trajectories is observed in AD ...individuals. However, genetic predictors of domain‐specific cognitive performance remain undiscovered. We investigated cross‐sectional and longitudinal genetic architecture of harmonized memory, executive function, and language scores within and across ancestry groups.
Method
Using data from 7 cohorts of cognitive aging and AD, individuals >60 years at baseline were included (mean age at baseline = 71.2). Cognitive scores for memory, executive function, and language were harmonized using latent variable models. Slopes for cognitive scores were calculated for each domain with linear mixed‐effects models. GWAS was performed on each cognitive domain for individual cohorts, both at baseline and longitudinally. Models covaried for baseline age, sex, and the first three genetic principal components. Individual models were assessed among non‐Hispanic Whites (NHW) (N = 26,455), non‐Hispanic Blacks (NHB) (N = 3,410), and cross‐ancestry (NHW + NHB) (N = 29,865). Results were meta‐analyzed across cohorts.
Result
We identified six genetic loci showing a genome‐wide significant effect on cognition, in addition to well‐established associations between cognition and APOE: three loci in NHW, one locus in NHB, and two loci in cross‐ancestry results. In NHW, a chromosome 2 locus (rs6733839) near BIN1, a previously reported AD risk gene, was associated with longitudinal memory performance (MAF = 0.40, p = 3.36E‐08). Additionally, in NHW, two chromosome 2 loci (rs2940785 and rs2972059) were associated with memory decline (MAF = 0.05, = 3.92E‐09; MAF = 0.05, p = 5.06E‐09, respectively). Despite the small sample size, a chromosome 10 locus (rs77595416) was associated with longitudinal executive function in NHB (MAF = 0.01, p = 7.68E‐09). When analyzing cross‐ancestry results, two chromosome 2 loci near BIN1 (rs4663105 and rs6733839) were associated with memory decline (MAF = 0.44, p = 2.65E‐08; MAF = 0.40, p = 9.48E‐10, respectively).
Conclusion
We elucidate novel and replicate known genetic predictors of domain‐specific cognition in older adults. Furthermore, we show that genetic architecture of multiple cognitive domains in older adults differs by ancestry, highlighting SNPs observed in longitudinal memory (NHW and cross‐ancestry) and executive function (NHB). While replication is warranted, our results underscore the contribution of genetic predictors beyond APOE to cognitive decline and suggest the importance of ancestry‐specific analyses of cognition.
